Infantile Haemangiomas

• Hemangioma of infancy
• Hemangioma

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• The most common benign soft tissue tumor of infancy.
• Characteristic growth pattern: early proliferation followed by gradual, spontaneous involution and variable residual skin changes.
• Distinct histopathologic and immunohistochemical features that differentiate infantile hemangiomas (IHs) from other vascular anomalies in children.
• May be associated with extracutaneous findings when occurring at certain anatomic sites (e.g. the face, neck, lumbosacral area), especially when lesions have a segmental pattern.
• Management is tailored to each patient as suggested in published guidelines.
• Systemic β-blockers are first-line therapy for most children with complicated hemangiomas.

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• IHs are benign proliferations of endothelial cells and their supporting tissues; represent the most common tumors arising in the neonatal period.
• Characterized by significant growth during the first several months of life, followed by slow spontaneous involution over the ensuing years.
• This natural history differentiates them from vascular malformations.
• Studies highlighting the potential roles of specific IH stem cells and hypoxia have provided new insights into pathophysiology.

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• "Infantile hemangioma" and "hemangioma of infancy" describe a specific group of vascular tumors arising during infancy with characteristic clinical/histologic features.
• IHs recognized in medical literature for centuries; older names include strawberry nevus and capillary hemangioma.
• Term "hemangioma" was historically applied broadly to congenital and acquired vascular anomalies (including malformations) without regard to biologic behavior.
• 1982 — Mulliken and Glowacki¹ first proposed categorizing vascular birthmarks according to biologic and clinical behavior.
• The International Society for the Study of Vascular Anomalies (ISSVA) has modified/updated this classification periodically, including genetic bases of vascular anomalies².
• Under this scheme, vascular birthmarks divide into three categories:
• Vascular tumors — characterized by cellular proliferation (IH, pyogenic granuloma, tufted angioma, kaposiform hemangioendothelioma, etc.).
• Vascular malformations — believed to represent errors in vascular morphogenesis; noted in the neonatal period but do NOT rapidly proliferate in the first year nor resolve spontaneously.
• A smaller group of "provisionally unclassified" lesions.

Biologic Classification of Vascular Birthmarks (ISSVA)

• Vascular tumors
• Benign:
• Infantile hemangioma
• Congenital hemangioma (rapidly involuting, non-involuting, partially involuting)
• Tufted angioma
• Pyogenic granuloma
• Spindle cell hemangioma
• Others
• Locally aggressive or borderline:
• Kaposiform hemangioendothelioma
• Others, e.g. retiform or composite hemangioendothelioma
• Vascular malformations
• Simple:
• Capillary malformations (CMs)
• Venous malformations (VMs) — common, glomuvenous, others
• Lymphatic malformations (LMs) — common: macrocystic, microcystic, mixed; others
• Arteriovenous malformations, arteriovenous fistula (AVMs, AVFs; high flow)
• Combined: CVM, CLM, LVM, CAVM, CLAVM, others
• Of major named vessels
• Associated with other anomalies: Sturge–Weber syndrome, Klippel–Trenaunay syndrome, others
• Provisionally unclassified
• Angiokeratomas
• Multifocal lymphangioendotheliomatosis with thrombocytopenia
• Others
• Abbreviations: CAVM = capillary–arteriovenous malformation; CLAVM = capillary–lymphatic–arteriovenous malformation; CLM = capillary–lymphatic malformation; CVM = capillary–venous malformation; LVM = lymphatic–venous malformation.
• Vascular malformations discussed in Ch. 104; other vascular tumors in Ch. 114.

Differences Between Infantile Hemangiomas and Vascular Malformations

• Clinical
• IH: usually absent at birth or subtle precursor lesion present (only occasionally well formed); rapid proliferation in first 2–5 months of life; spontaneous involution over years.
• Vascular malformation: usually evident at birth; slower expansion proportionate to child's growth; persists into adulthood.
• Epidemiology
• IH more common in: girls (2–5:1); premature and/or low-birth-weight infants; infants whose mothers were older, underwent chorionic villus sampling, or had preeclampsia.
• Vascular malformation: no sex or gestation predilection.
• Pathology
• IH proliferating: endothelial cell hyperplasia, lobule formation, mast cells, prominent basement membrane.
• IH involuting: fibrofatty tissue replacement, decreased mast cells when fully involuted.
• Vascular malformation: dependent upon type, often irregular vascular channels.
• Immunohistochemistry
• IH: positive for GLUT1, Lewis Y antigen, merosin, FcγRII, Wilms tumor protein 1 (WT1).
• Vascular malformation: negative for GLUT1, Lewis Y antigen, merosin, FcγRII, WT1.

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• IHs arise during the first year of life and are the most common tumor of infancy.
• Develop in 4%–5% of infants, usually noted within the first several weeks of life.
• May occur more commonly in White infants than other racial groups.
• Female:male ratio of 2–5:1 in multiple retrospective and prospective studies conducted in dermatology practices; however, a hospital-based prospective birth-cohort study found no female predominance.
• A higher female:male ratio of 7–9:1 reported for patients with severe, complicated IHs.
• Prematurity: IHs develop more frequently in premature infants.
• Low birth weight is an independent risk factor.
• 25%–30% of infants with birth weight <1000 g.
• 15% of infants with birth weight 1000–1500 g.
• Placental insufficiency factors (e.g. preeclampsia, placenta previa) are associated with IH development.
• Prematurity and multiple gestation pregnancies linked with multifocal IHs.
• Threefold increased incidence in infants born following chorionic villus sampling compared to amniocentesis or no prenatal instrumentation.
• Higher maternal age also associated with hemangioma development.
• Typically sporadic; family history reported in up to a third of patients, but frequent occurrence in the general population makes true familial incidence hard to assess; no specific genes consistently implicated.

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• IHs represent localized/regional abnormal vascular development and proliferation.
• Development involves:
• De novo formation of vessels from multipotent hemangioma-derived stem cells (HemSCs) and endothelial progenitor cells (vasculogenesis).
• Formation of new vessels from existing ones (angiogenesis).
• Other cell types (monocytes, fibroblasts, pericytes, mesenchymal cells, adipocytes, mast cells) influence endothelial cell proliferation and may contribute to formation/involution.

Placental Origin Hypothesis

• Overlapping immunohistochemical phenotype of hemangioma cells and human placental endothelium suggests hemangioma cells may be of placental origin or differentiate toward placental microvascular phenotype.
• North et al.¹²,¹³: GLUT1 (glucose transporter protein-1) is expressed by IHs during all phases (proliferating, involuting, involuted) as well as by placenta, but not other vascular tumors or malformations.
• Additional placenta-associated vascular antigens present in hemangioma specimens and placental chorionic villi (but absent in normal skin/subcutis microvessels): merosin, FcγRII, Lewis Y antigen.
• However, hemangiomas do NOT express placental trophoblastic markers (e.g. human placental lactogen) — not thought to represent placental emboli.

Role of Hypoxia

• Supported by association with: hypoxic placental changes, prematurity/low birth weight (often from placental insufficiency), retinopathy of prematurity (GLUT1-positive, hypoxia-induced neovascularization), regional arterial insufficiency in PHACE(S) and LUMBAR syndromes.
• Hypoxia upregulates GLUT1 and VEGF, mobilizing endothelial progenitor cells.
• Hypoxia + estrogen synergistic effect on hemangioma endothelial cell proliferation in vitro — potential explanation for female predilection.
• HIF-1α and downstream effectors upregulated during proliferative phase.

Signaling Pathways

• VEGF (VEGF-A) signaling: shift from VEGFR-1 (high affinity, weak signal) to VEGFR-2 (strongly stimulates endothelial proliferation).
• VEGFR-2 signaling activates PI3K-mTOR pathway → upregulates HIF-1α → increases VEGF.
• Sirolimus (rapamycin), an mTOR inhibitor, reduces proliferation of hemangioma endothelial cells in vitro.
• Increased expression of endothelial cell-specific Tie-2 tyrosine kinase receptor and dysregulated angiopoietin-2 production — may promote angiogenesis and inhibit vessel maturation.
• Notch pathway: mediates differentiation of HemSCs into pericytes/vascular smooth muscle cells, which have pro-angiogenic properties supporting IH development.
• Renin–angiotensin system (RAS): implicated in IH proliferation via activation of angiotensin II receptor 2; β-blocker treatment of IH reduces plasma renin levels.

Genetic Factors

• Somatic mutations reported in genes encoding proteins involved in VEGF signaling (e.g. VEGFRs) and other vascular-development pathways.
• Heterozygous germline mutations in VEGFR2 and ANTXR1 (anthrax toxin receptor 1, encodes integrin-like endothelial receptor) identified in a small subset — may represent hemangioma predisposition factors.

Factors Influencing Natural History

• Proliferative phase markers: PCNA (proliferating cell nuclear antigen), increased VEGF and bFGF (basic fibroblast growth factor); other angiogenesis mediators, perivascular extracellular matrix proteins, and matrix-remodeling enzymes at higher levels.
• Mechanisms governing transition from proliferation to involution not fully understood.
• Involuting hemangiomas: increased expression of angiogenesis inhibitors and apoptosis promoters.
• Mesenchymal stem cells may contribute to endothelial proliferation during growth phase or differentiate into adipocytes contributing to fibrofatty residua during involution.

Markers of Proliferating and Involuting Hemangiomas

• Proliferative phase
• General proliferation markers, e.g. PCNA
• VEGF, bFGF* †
• Monocyte chemoattractant protein-1 †
• Adhesion molecules on endothelial cells — E-selectin, ICAM-3 †
• Matrix metalloproteinase-2 and -9 (extracellular matrix remodeling) ‡
• Vitronectin (perivascular ECM)
• Indoleamine 2,3-dioxygenase (inhibits T cell activation)
• Apoptosis inhibitors
• Involution
• Interferon-regulated gene products (interferons inhibit angiogenesis)
• bFGF (early in involution)
• Increased mast cells (early in involution)
• Tissue inhibitor of matrix metalloproteinases-1 (inhibits angiogenesis)
• Apoptosis promoters
• *VEGF and bFGF, but NOT the angiogenesis inhibitor interferon-β, are also expressed by hyperplastic epidermis overlying proliferating hemangiomas.
• †Angiogenesis mediators.
• ‡Increased levels also found in blood and urine.
• LYVE-1 (lymphatic vessel endothelial hyaluronan receptor) identified in perivascular dendritic cells in hemangiomas of various stages.

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Presentation

• Most IHs have a typical presentation/growth pattern; lesions usually apparent during first few weeks of life.
• Proportion of "congenital" IHs in published series ranges from 15% to 60%.
• IHs evident at birth most often appear as precursor lesions (apparent in up to 65% of IHs); occasionally present as relatively well-formed typical IHs that then proliferate then involute.
• Precursor lesions include: telangiectasias surrounded by a vasoconstricted halo, areas of pallor, pink macules, blue bruise-like patches.
• Pink macules/patches may mimic a capillary malformation — repeat examination over ensuing weeks essential.
• RICH/PICH/NICH (rapidly involuting, partially involuting, non-involuting congenital hemangiomas) are distinct entities discussed later.
• Occasionally, ulceration in the diaper area, other skin folds, or lip may herald IH onset — may be confused with bacterial/viral infection in newborn; continued observation clarifies diagnosis.
• Dermoscopy: red lacunae separated by white septae in superficial IHs; violaceous to blue lacunae in deeper IHs.
• May occur anywhere on skin/mucosa; most commonly develop on the trunk overall, but ~50% of IHs presenting to a pediatric dermatologist are on the head and neck.

Depth-Based Types

• Superficial hemangiomas: upper dermis; bright red during proliferating phase; finely lobulated surface; "strawberry hemangioma."
• ~50%–60% of IHs (most common type).
• Deep hemangiomas: deep dermis and/or subcutis; often not apparent in immediate newborn period, becoming evident weeks–months after birth; warm, ill-defined, light blue–purple masses with minimal/no overlying skin changes — more difficult to diagnose.
• Dilated veins/telangiectasias overlying may be a clue.
• Larger deep hemangiomas often have significant arterial blood supply during proliferation; Doppler ultrasonography can detect high flow.
• 15% of IHs.
• Mixed hemangiomas: both superficial and deep components — well-delineated red vascular plaque overlying a broader, poorly circumscribed violaceous/light blue nodule.
• 25%–35% of IHs.
• ~25% of patients have multiple lesions, occasionally associated with hemangiomas in liver/other internal organs.

Pattern of Involvement

• Focal — arising from a single localized nidus (majority of IHs); facial lesions may show predilection for embryonic fusion lines.
• Segmental — covering a broad area/developmental unit in a "plaque-like" manner.
• Indeterminate — difficult to classify; may represent partial segmental lesions respecting anatomic boundaries.
• Segmental facial hemangiomas resemble embryonic facial prominences (differ most on upper face); 4 primary facial segments: S1 (frontotemporal), S2 (maxillary), S3 (mandibular), S4 (frontonasal) (based on prospective study n=165).
• Involvement may be incomplete; some encompass more than one segment.
• A C-shaped pattern from posterior auricular area to posterolateral scalp also observed.
• Segmental hemangiomas often begin as broad patches of confluent/reticulated erythema and/or telangiectasias; within weeks, bright red papules/plaques arise within the "field."
• Segmental hemangiomas more likely associated with regional extracutaneous anomalies (PHACE(S), LUMBAR syndromes).
• On extremities: smaller segmental hemangiomas typically spare the distal digits ("biker glove" pattern); larger lesions encompassing distal digits have higher risk of extracutaneous anomalies.
• Rhabdomyomatous mesenchymal hamartomas (papule/atrophic plaque in midline anterior neck/trunk or sacrum) described in association with segmental hemangiomas.

Natural History

• Phases: early proliferation (rapid increase in size), late proliferation (continued growth at slower rate), plateau (existence as distinct phase debated), involution.
• Hemangiomas "mark out their territory" early, then undergo primarily volumetric rather than centrifugal growth.
• During proliferative phase: become warmer, firmer; superficial surface may appear tense; mixed/deep lesions feel firmer and look larger when infant crying/active.
• Deep hemangiomas proliferate longer than superficial ones; deep component of mixed lesions may continue growing after superficial component plateaus.
• Majority reach 80% of final size by end of early proliferative phase, at a mean age of 3 months; growth usually most rapid from 5 to 8 weeks of age.
• Small minority grow after 9 months of age (rarely as late as ≥3 years) — tend to have deep component and/or segmental morphology; parotid gland area lesions particularly prone to this behavior.
• IH with minimal or arrested growth (IH-MAG) (previously "abortive"/"reticular"): little/no growth beyond patches of reticulated erythema with coarse/fine telangiectasias, often on background of pallor.
• Proliferative component (if present) involves <25% of surface area, often small red papules at periphery.
• Eczematous dermatitis localized to IH-MAG described.
• Favor the lower body; may develop recalcitrant ulceration or (if larger/segmental) be associated with LUMBAR or PHACE(S).
• GLUT1-positive; involute at pace similar to classic IHs, though larger ectatic vessels may persist.
• Involution: may begin as early as first year of life, continues for several years.
• Color change from bright red to gray–purple and surface flattening are earliest signs in superficial lesions; deeper lesions become less firm.
• Classic studies: 30% involute fully by 3 years, 50% by 5 years, 70% by 7 years, >90% by 9 years.
• More recent studies: median age of completed involution is 36 months, with >90% showing no further improvement after 4 years of age.
• Some involute completely; others leave: residual telangiectasias, atrophy/anetoderma, fibrofatty tissue, redundant skin, or (if previously ulcerated) scarring.
• Risk factors for more prominent residual sequelae: abrupt "step" border, "cobblestoned" surface, mixed IH subtype.

Complications

• Majority are small, requiring little/no intervention; some problematic due to size, location, or associated anomalies.
• Age and growth pattern help determine risk/need for systemic therapy.

Ulceration

• Most common complication; occurs in up to 10% of all IHs.
• Greatest tendency: lip, anogenital region, other skin folds (e.g. neck).
• More common in large, mixed, or segmental hemangiomas; up to 30% of segmental extremity lesions ulcerate.
• IHs-MAG prone to (potentially recalcitrant) ulceration.
• Occurs most commonly during proliferative phase; most ulcers develop within first 6 months of life.
• Whitish discoloration in infants <3 months may signal impending ulceration.
• Causes pain, increases infection risk, results in scarring; bleeding rarely occurs and can usually be controlled with firm pressure.
• Large size, segmental morphology, and greater ulcer surface area associated with longer healing times.

Disfigurement / Functional Interference

• Large hemangiomas can distort tissues, interfere with function, cause long-term sequelae; regional extracutaneous abnormalities may occur (mostly with segmental lesions).
• High-output congestive heart failure: rare complication, primarily with extensive hepatic hemangiomas.
• Periocular hemangiomas: astigmatism (compressing globe, deforming cornea → asymmetric refractive errors); visual axis obstruction/orbital muscle invasion → light-deprivation amblyopia and strabismus, respectively; proptosis (rare) may cause corneal exposure. Ophthalmologic evaluation at baseline with follow-up during proliferative stage recommended.
• Nasal tip hemangiomas: deep/mixed lesions distort underlying cartilage, leave significant fibrofatty residua — "Cyrano-nose" deformity may require reconstructive surgery. Superficial lesions along the columella may ulcerate, destroying underlying cartilage (heralded by a horizontal crease in the inferior columella).
• Lip hemangiomas: often superficial/mixed; painful ulceration common with proliferation → feeding difficulties; friction/moisture contribute. Distortion of vermilion border or lip lengthening can require surgical correction.
• Pinna hemangiomas: may ulcerate, become infected, cause scarring/structural distortion; conductive hearing loss from external auditory canal obstruction.
• Breast hemangiomas (girls): may affect underlying breast bud → breast asymmetry residua; early surgical intervention not advised (may affect normal breast development).
• Anogenital hemangiomas: often complicated by painful ulceration; wound care difficult.
• Limb hemangiomas: may ulcerate; residual excess tissue and rarely limb-length discrepancy can persist.

Extracutaneous Involvement

• Large head/neck hemangiomas, most commonly segmental lesions >5 cm diameter, often associated with extracutaneous anomalies.
• Relationship between facial hemangiomas and structural/vascular CNS anomalies recognized >45 years ago.
• 1996 — acronym PHACE(S) syndrome coined:
• P — Posterior fossa and other structural brain malformations
• H — Hemangioma
• A — Arterial anomalies of cervical and cerebral vessels
• C — Cardiac defects (especially coarctation of the aorta)
• E — Eye anomalies
• (S) — Sternal defects and supraumbilical raphe
• Additional less common features: impaired hearing, dysphagia, speech/language delay, dental anomalies, endocrine abnormalities (hypopituitarism, hypothyroidism).
• Diagnostic criteria established by multidisciplinary group in 2009, updated 2016.
• Prospective study of 108 infants (age <1 year) with large facial hemangiomas (≥22 cm²): 31% had PHACE(S) syndrome.
• 91% of affected individuals had more than one extracutaneous manifestation (major ± minor).
• Most common findings: cerebrovascular (91%), cardiovascular (67%), structural brain (52%) anomalies.
• Cerebrovascular anomalies typically ipsilateral to the hemangioma, most commonly involving internal carotid artery — highlights need for head AND neck imaging.
• In other studies, prevalence of PHACE(S) among segmental IHs of head/neck as high as 58%.
• Cerebrovascular/cardiovascular changes may be progressive — potential complications: ischemic stroke, neurovascular sequelae in adulthood (e.g. atypical migraines, hearing loss).

Diagnostic Criteria for PHACE(S) Syndrome

• Definite PHACE(S):
• Hemangioma >5 cm diameter of the head (including scalp) PLUS 1 major criterion or 2 minor criteria
• Hemangioma of the neck, upper trunk, or trunk and proximal upper extremity PLUS 2 major criteria
• Possible PHACE(S):
• Hemangioma >5 cm diameter of the head (including scalp) PLUS 1 minor criterion
• Hemangioma of neck, upper trunk, or trunk and proximal upper extremity PLUS 1 major criterion or 2 minor criteria
• No hemangioma PLUS 2 major criteria
• Organ systems, major and minor criteria:
• Arterial — Major: anomalies of major cerebral or cervical arteries* (dysplasia†, hypoplasia, stenosis/occlusion, aberrant origin/course); persistent carotid–vertebrobasilar anastomosis (e.g. proatlantal segmental, hypoglossal, otic, trigeminal arteries); aneurysm of cerebral arteries.
• Structural brain — Major: posterior fossa anomalies (Dandy–Walker complex, other hypoplasia/dysplasia of mid or hind brain); midline anomalies; malformation of cortical development.
• Cardiovascular — Major: aortic arch anomalies; aberrant origin of subclavian artery ± vascular ring. Minor: ventricular septal defect; right/double aortic arch; systemic venous anomalies.
• Ocular — Major: posterior segment anomalies (persistent hyperplastic primary vitreous/persistent fetal vasculature, retinal vascular anomalies, optic nerve hypoplasia, morning glory disc anomaly). Minor: anterior segment anomalies (e.g. sclerocornea, cataract, coloboma, microphthalmia).
• Ventral or midline — Major: sternal defect/pit/cleft; supraumbilical raphe. Minor: hypopituitarism; ectopic thyroid; midline sternal papule/hamartoma.
• *Includes internal carotid artery; middle, anterior, or posterior cerebral artery; and vertebrobasilar system.
• †Includes kinking, looping, tortuosity, and/or dolichoectasia.

• Lower facial ("beard") hemangiomas: often mark airway hemangiomas, typically involving the subglottis.
• Risk of airway hemangioma estimated by extent of cutaneous involvement in this region (5 anatomic sites, each scoring 1 point).
• In a study of 16 children with a score ≥4, 63% had some degree of symptomatic airway involvement.
• Occasionally associated with segmental hemangiomas primarily involving upper face, or small hemangiomas in the "beard" area.
• Onset of respiratory symptoms (noisy breathing, biphasic stridor) ranges from weeks to months of age.
• Referral for otolaryngologic evaluation for lesions of concern.
• Midline lumbosacral hemangiomas: marker for occult spinal dysraphism.
• Risk of spinal dysraphism with isolated midline lumbosacral hemangioma or involuted residuum >2.5 cm diameter: ~35%.
• Increased risk factors: larger or ulcerated hemangioma; additional cutaneous markers (deviated gluteal cleft, lipoma, skin appendage).
• LUMBAR syndrome — most inclusive acronym for lower-body segmental IH associations:
• L — Lower body/lumbosacral hemangioma and lipomas or other cutaneous anomalies (e.g. "skin tags")
• U — Urogenital anomalies and ulceration of the hemangioma
• M — Myelopathy (spinal dysraphism)
• B — Bony deformities
• A — Anorectal and arterial anomalies
• R — Renal anomalies
• Also referred to as SACRAL syndrome (spinal dysraphism, anogenital anomalies, cutaneous anomalies, renal/urologic anomalies, angioma, in lumbosacral area) and PELVIS syndrome (perineal hemangioma, external genital malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, skin tag).

Evaluation of a Child with IHs for Possible Extracutaneous Involvement

• Segmental hemangioma → abdominal (hepatic) ultrasound, consider CBC, stool guaiac, urinalysis.
• Multiple (≥5) hemangiomas* → if within normal limits: serial examinations, treatment as indicated. If abnormal or multifocal/diffuse hepatic hemangiomas → TFTs, LFTs, α-fetoprotein level; consider echocardiogram/cardiac evaluation and abdominal MRI; referral to specialists as needed.
• *In infants ≤6–9 months of age and as clinically indicated in older infants.
• "Beard" hemangiomas → ENT evaluation, airway endoscopy.
• Head and/or neck (exclude PHACE(S) syndrome):
• Initial evaluation (preferably age <3 months): physical exam of affected region; ultrasound (with Doppler) of abdomen, pelvis, and (if age <3 months) spine.
• Additional evaluation (preferably age 3–6 months unless indicated): ophthalmologic exam; echocardiogram/cardiac evaluation; MRI/MRA of head and neck.
• Evaluation of other organ systems as clinically indicated.
• Lower body and/or lumbosacral (exclude LUMBAR syndrome):
• If midline lumbar hemangioma or lipoma (or abnormal spinal ultrasound): MRI of spine, consider neurosurgical evaluation.
• If extensive diaper area involvement (or abnormal pelvic/renal ultrasound): consider urologic evaluation.
• If extensive limb involvement: orthopedic evaluation and additional imaging as clinically indicated.
• Serial examinations, additional evaluation and treatment as indicated.

Multifocal, Visceral, and Other Extracutaneous Involvement

• Multifocal lesions: found in 10%–25% of infants with hemangiomas; may be associated with visceral involvement.
• Most infants with internal + skin involvement have many small superficial cutaneous hemangiomas (a few mm to a few cm).
• Historical terms "diffuse" and "benign" neonatal hemangiomatosis used for multiple cutaneous hemangiomas with or without visceral lesions, respectively — but some reported cases actually represented other anomalies (e.g. multifocal lymphangiomatosis with thrombocytopenia).
• Preferred term now: multifocal infantile hemangiomas with or without extracutaneous hemangiomas.
• Liver is by far the most common site of internal hemangiomas in multifocal IHs.
• Because greater number of cutaneous IHs increases risk of hepatic involvement, abdominal ultrasonography recommended when ≥5 skin lesions present.
• Rarely, infants with a large IH or fewer than 5 small IHs have liver involvement.
• Liver hemangiomas classified as: focal, multifocal, or diffuse.
• Focal hepatic hemangiomas likely distinct from IHs, undergoing early involution similar to RICH.
• Multifocal/diffuse associated with risk of high-output cardiac failure (arteriovenous or arterioportal shunts), hypothyroidism, and abdominal compartment syndrome (from massive hepatomegaly).
• Management requires interdisciplinary care: serial ultrasounds, clinical assessments, laboratory evaluation, treatment as indicated.
• Extracutaneous hemangiomas occasionally occur with a single large cutaneous hemangioma (usually segmental facial), with or without PHACE(S).
• Segmental cutaneous hemangiomas may be associated with segmental GI-tract hemangiomas, most often in distribution of the superior mesenteric artery, potentially complicated by bleeding.
• CNS IHs: very rare, typically intracranial/intraspinal extension of an overlying (often segmental) IH; associated hydrocephalus reported, but invasion into CNS parenchyma does NOT typically occur.
• Additional rare internal sites: mediastinum, lungs.
• Consumptive hypothyroidism: increased levels of type 3 iodothyronine deiodinase (deactivates thyroid hormone) in proliferating hemangioma tissue.
• Can cause hypothyroidism in infants with large-volume proliferative-phase lesions.
• Difficult to correct due to consumptive nature; resolves as tumor regresses.
• Neonatal screening inadequate (hemangiomas typically only beginning to develop at that time).
• Usually associated with hepatic hemangiomas, but also described with large parotid-area hemangiomas; enzyme activity noted in cutaneous hemangiomas too.
• Recommend considering hypothyroidism evaluation in infants with large cutaneous or hepatic hemangiomas.

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• Most superficial and mixed IHs diagnosed clinically.
• Ultrasonography or MRI helpful for confirming diagnosis/extent of deep IHs lacking superficial changes.
• Important to consider phase of growth — proliferating hemangiomas differ radiographically from involuting/involuted ones.
• MRI with contrast = most useful imaging technique to define extent/tissue characteristics of vascular anomalies; contrast helps differentiate hemangioma from other tumors.
• If MRI doesn't confirm diagnosis or malignancy is a concern, histologic examination recommended.
• MRI/MRA also used to detect internal-organ hemangiomas and other structural abnormalities (CNS malformations, arterial anomalies).

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• Histopathologic features correlate with stage of hemangioma development.
• IHs may extend from superficial dermis to deep subcutaneous tissue; in some locations, may involve surrounding tissues (salivary glands, muscle).
• Proliferating hemangiomas: well-defined non-encapsulated masses of proliferating plump endothelial cells and pericytes; small vascular lumens may be noted focally (lumen formation harder to appreciate early).
• Later in proliferating stage: lobules of endothelial masses separated by fibrous septae become prominent; larger feeding/draining vessels within septae; mitotic figures and apoptotic bodies may be present.
• Abnormal mitotic figures NOT typical, but mitotic activity and mild nuclear pleomorphism may be present and should NOT be a cause for concern if other typical features present.
• Increased mast cells often present during proliferation; some studies found even higher numbers during early involution.
• Involution phase: flattening of endothelium, reduced mitotic figures; vessels decrease in number, lose tightly packed appearance; fibrous and fatty tissue separates vessels within/between lobules; feeding/draining vessels within septae may persist.
• Fully involuted lesions: fibrofatty tissue with a few persistent vessels at former tumor lobule/septae sites.
• Immunohistochemistry:
• High GLUT1 immunoreactivity in endothelia of IHs at ALL phases; absent in most other vascular tumors/malformations.
• WT1 (Wilms tumor 1) expression observed in IH but NOT vascular malformations, EXCEPT arteriovenous malformations.
• Other placenta-associated vascular proteins present in IHs but absent in vascular malformations and pyogenic granulomas: FcγRII, merosin, Lewis Y antigen.
• These placental markers also absent in normal vessels of skin and subcutis.

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• Superficial/mixed hemangiomas usually diagnosed clinically.
• Precursors and early proliferating lesions may be misdiagnosed as capillary malformations or telangiectasias.
• Pyogenic granulomas (PGs) — mimic superficial hemangioma but usually arise after the first few months of life, are typically pedunculated, and tend to bleed.
• Other vascular lesions of infancy in the differential: tufted angioma, multifocal lymphangioendotheliomatosis with thrombocytopenia, infantile hemangiopericytoma, spindle cell hemangioma, verrucous venulocapillary malformation ("verrucous hemangioma"), eccrine angiomatous hamartoma.
• Deep hemangiomas — greater diagnostic challenge; radiographic evaluation helpful. Differential: venous, lymphatic, or combined venous–lymphatic malformation; congenital hemangioma (RICH/NICH); kaposiform hemangioendothelioma.
• Kasabach–Merritt phenomenon (KMP): potentially life-threatening thrombocytopenic coagulopathy, typically first months to year of life, rapidly enlarging ecchymotic mass; now known to be primarily associated with kaposiform hemangioendotheliomas and less often tufted angiomas — NOT IHs as historically assumed.
• Congenital fibrosarcoma: often firm, blue–purple, may have ectatic superficial veins → misdiagnosis as hemangioma; some patients present with disseminated intravascular coagulation, further confusing picture.
• Other neoplasms that may have vascular appearance (overlying telangiectasias or blue–red color): rhabdomyosarcoma, neuroblastoma, primitive neuroectodermal tumor, lymphoblastic lymphoma, dermatofibrosarcoma protuberans.
• Additional entities mistaken for hemangioma:
• Infantile myofibromatosis — solitary or multiple red to pink plaques/nodules.
• Lipoblastoma — enlarging skin-colored or (less often) erythematous mass.
• Nasal glial heterotopia — classically congenital blue–red mass on bridge of the nose.
• Radiographic studies (especially MRI) may help differentiate; histologic examination indicated if diagnosis unclear or lesions atypical.

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• IHs manifest across a wide spectrum of clinical severity; management individualized.
• Hemangioma Activity Scale and Hemangioma Severity Scale developed to objectively assess IHs and response to therapy.
• Active intervention recommended for IHs with greater risk of local/systemic complications.
• Major goals of management:

1. Preventing or reversing life- or function-threatening complications.
2. Treating ulcerations.
3. Preventing permanent disfigurement.
4. Minimizing psychosocial distress to patients and families.
5. Avoiding overly aggressive, potentially scarring procedures for lesions with strong probability of involuting without significant residua.

Reasons to Consider Systemic Therapy for IHs

• Threatened vital functions: vision; airway.
• Increased potential for disfigurement: nasal tip/columella; lip (especially crossing vermilion border); large (≥2 cm)/rapidly growing lesion, especially on the face (>1 cm if age ≤3 months) or with an abrupt "step" border; breast (especially involving the nipple in a girl).
• Recalcitrant/severe ulceration.
• High-output cardiac failure.

Active Non-Intervention

• Small, uncomplicated hemangiomas have excellent prognosis; often managed with active non-intervention, especially extrafacial sites.
• Even small, seemingly trivial lesions may be troubling to parents.
• Includes addressing parental concerns, discussing natural history, treatment indications/types, periodic clinical assessment and photography.
• Many parents fear bleeding — review of superficial bleeding care and reassurance is worthwhile.

Management of Ulceration

• Most frequent complication; management directed at healing, preventing infection, reducing pain.
• Multiple modalities often used concurrently; no single therapy proven most effective.

Wound Care

• Small superficial ulcerations managed with local wound care.
• Saline compresses to gently debride thick crusts.
• Topical antibacterial ointments (e.g. mupirocin) for occlusive/antimicrobial effect; bacterial culture if infection signs develop.
• Occlusive dressings (hydrocolloid, foam, silicone-based) aid healing/pain control; applied after topical antibiotic or petrolatum.
• Thin hydrocolloid dressings favored (ease of application over curved surfaces, can leave in place for days).
• Petrolatum-impregnated gauze inexpensive, helpful for perineal ulcers, but needs frequent changes.

Specific Therapy

• Topical timolol can aid healing of small ulcerated IHs — caution regarding systemic absorption.
• Oral propranolol: useful for extensive ulcers or those failing local therapy.
• Study (ulcers present mean 7 weeks): median time to healing after starting propranolol = 4 weeks; most patients achieved pain relief within 15 days.
• Early propranolol may help prevent ulceration in high-risk locations, but precipitation/worsening of ulceration also described.
• Low-dose start with slow escalation recommended for IHs with ulceration or high risk; retrospective study found ulcer healing time shorter with propranolol dose ≤1 mg/kg/day vs higher doses.
• Pulsed dye laser (PDL): used, especially combined with other modalities; uncontrolled studies showed healing/pain resolution after 2–3 treatments; others found mixed results (50% improvement, 5% worsening).
• Excisional surgery: may be considered for small or pedunculated ulcerated lesions.

Pain Control

• Local wound care (especially occlusive dressings) provides some relief.
• Oral acetaminophen and topical lidocaine 2%–5% ointment may help.
• Lidocaine ointment used sparingly (max pea-sized amount) to prevent systemic toxicity.
• Eutectic mixture of local anesthetics NOT recommended — should not be applied to eroded/ulcerated skin.
• Severe cases may require pain management specialist consultation.

Local Therapies

Topical β-Blockers

• Timolol maleate (non-selective β-blocker) can benefit small superficial IHs <1 mm thick.
• Available as 0.5% solution and 0.5% gel-forming solution (GFS, extended-release); 1 drop (0.25 mg) twice daily of the GFS most commonly used.
• RCT: this dosing effective/safe for small (<2.5 cm), thin, non-ulcerated cutaneous IHs in infants 5–24 weeks of age, with benefit after 8–16 weeks of treatment.
• Pharmacokinetic study: as hemangiomas with a prominent superficial component increase in thickness, higher plasma concentrations of topically applied timolol observed.
• No established treatment guidelines, but recommended max: 2 drops of timolol 0.5% GFS daily, or <0.25 mg/kg/day.
• Despite systemic absorption, generally well tolerated; serious adverse events rare.

Intralesional Corticosteroids

• Historically common for localized IHs; now used infrequently given β-blocker efficacy.
• Triamcinolone <3 mg/kg per treatment session may be used for selected small, focal hemangiomas.
• Serious complications: retinal and ophthalmic artery occlusion leading to permanent vision loss, local atrophy and necrosis — has limited use in the periorbital area.

Systemic Therapies

Systemic β-Blockers

• Serendipitous discovery of propranolol as IH treatment in 2008 — revolutionized management; now first-line systemic therapy.
• 2014 — propranolol (Hemangeol™) became the first FDA-approved treatment for IHs.
• Effective in halting growth/expediting regression of cutaneous, ocular, airway, hepatic IHs, and complications like ulceration.
• Mechanisms of action (multifaceted):
• Color change (red→purple) and softening within first few days: immediate vasoconstrictive effects via β2-adrenergic receptors on hemangioma pericyte cells.
• Subsequent progressive volume/redness reduction: decreases in serum VEGF, bFGF, and renin; induction of endothelial cell apoptosis.
• Compared to systemic corticosteroids: superior efficacy and more favorable side-effect profile.
• Adverse effects:
• Potentially serious (uncommon): hypotension, bradycardia, hypoglycemia, bronchospasm.
• β-blockers may mask early signs of hypoglycemia — infants should be fed in conjunction with dosing.
• More common: sleep disturbances (restless sleep, nightmares), cold extremities, diarrhea, somnolence (especially first few days).
• Rare: hyperkalemia associated with propranolol treatment of large ulcerated hemangiomas.
• Long-term studies: no evidence of cognitive, developmental, or growth impairment in 4- to 7-year-old children who received propranolol during infancy.
• Patients at risk of PHACE(S) should be evaluated for cardiovascular/cerebrovascular anomalies before treatment (theoretical hypotension risk); most can still be treated successfully with propranolol, but may need combined management with cardiologists/neurologists, cautious dose escalation if increased stroke risk.
• History of airway reactivity/asthma may not be an absolute contraindication but requires closer monitoring and pulmonology consultation.

Administration of Propranolol for IHs

• Counseling for parents:
• Discuss potential risks: bradycardia, hypotension, hypoglycemia, sleep disturbances, bronchospasm.
• Review signs of hypoglycemia: early (may be masked by β-blockade) — sweating, rapid heart rate, shakiness, fussiness; late — lethargy, poor feeding, hypothermia, seizures.
• Administer during or immediately after a feeding; twice-daily doses ≥9 hours apart.
• Lower dose or suspend therapy during intercurrent illnesses with decreased oral intake or vomiting.
• Provide written anticipatory guidance (pedsderm.net resource referenced).
• Assessment of risk for β-blocker complications:
• Standard risk: age ≥5 weeks (corrected for prematurity); normal birthweight and weight gain; IH pattern/distribution not at risk for PHACE; normal cardiovascular/respiratory exam/history; caregiver able to adhere to outpatient protocols.
• Higher risk: age <5 weeks (corrected); IH pattern/distribution at risk for PHACE (hemangioma ≥5 cm diameter on head or upper body); history of recent/persistent hypoglycemia; cardiovascular disease, reactive airway disease/bronchospasm, or brain malformation; extensive hepatic hemangiomas; first-degree relative with congenital heart disease, sudden death, or arrhythmia; maternal history of connective tissue disorder.
• For at-risk patients: MRI/MRA of head/neck and echocardiogram to exclude arterial/cardiovascular anomalies; consult neuroradiologist, neurologist, and/or cardiologist if abnormal.
• Contraindications: bradycardia (<80 beats/minute), blood pressure <50/30 mmHg, >1st degree heart block, decompensated heart failure. Reactive airway disease/bronchospasm = relative contraindication (may need pulmonology consult).
• Dosing and course:
• Initial: usually ~1 mg/kg/day divided into 2 (or 3) doses.
• Target: 2–3 mg/kg/day divided into 2 (or 3) doses; may be lower (~1 mg/kg/day) for ulcerated lesions; FDA-approved maximum = 3.4 mg/kg/day.
• For a proliferating IH, treatment typically continued 6–12 months, depending on clinical setting/course.
• Dose adjusted for weight gain to maintain goal dose/kg.
• Taper over 2–4+ weeks before discontinuing, primarily to assess for rebound growth.
• Dose typically increased in increments of 1 mg/kg/day weekly (outpatient) or after 1–3 doses (inpatient) until target reached; lower starting/target dose and slower escalation for higher-risk patients.
• At-home initiation (e.g. via telemedicine): starting dose 0.5 mg/kg/day, increased by 0.5 mg/kg/day every 3–4 days until target reached.
• Longer duration may be required for IHs with prolonged or rebound growth.
• Monitoring:
• Outpatient initiation of therapy.
• FDA recommendations: monitor heart rate and blood pressure for 2 hours after initial dose or significant dose increase.
• Measure heart rate and blood pressure every 4–8 weeks on stable dose.
• Consider brief inpatient stay (1–2 days) with telemetry for initiation if <5 weeks corrected age and/or complications (cardiovascular/cerebrovascular anomalies).
• A multicenter retrospective study found in-office vital sign monitoring at initiation/dose escalation rarely changed management and did not predict adverse events.
• Dosing chart provided for FDA-approved Hemangeol™ 4.28 mg/ml solution; generic propranolol 20 mg/5 ml (4 mg/ml) solution also available.
• Rebound growth: ~25% of IHs undergo rebound growth after propranolol cessation, higher risk if lesion is deep or therapy discontinued before 9 months of age.

β-Blocker Alternatives

• Hydrophilic β-blockers that do NOT cross the blood–brain barrier (unlike lipophilic propranolol) may produce fewer CNS effects (e.g. sleep disturbance):
• Atenolol (β1-selective)
• Nadolol (non-selective)
• Neither is FDA-approved for IH treatment.
• RCTs show efficacy/safety similar to propranolol, with faster response to nadolol.
• Nadolol excreted primarily in feces — monitor bowel movement frequency; hold medication if substantial constipation.
• A study found the R(+) enantiomers of propranolol and atenolol (which lack β-blocker activity) inhibited formation of IH-like blood vessels from hemangioma stem cells in a murine xenograft model — suggests possible future utility.

Systemic Corticosteroids

• Traditionally used for life- or function-threatening hemangiomas.
• Suppress VEGF production by HemSCs and inhibit vasculogenesis in a murine model.
• No longer first-line, but still occasionally used when β-blockers contraindicated or in combination with β-blockers (e.g. for airway or diffuse hepatic hemangiomas).
• Initial doses: equivalent to 2–3 mg/kg/day of prednisone, with variable duration, tapering schedules, and monitoring.
• Adverse effects: cushingoid facies, irritability, disrupted sleep, GI symptoms, hypertension, HPA-axis suppression, increased susceptibility to opportunistic infections.

Other Systemic Therapies

• Sirolimus (rapamycin): inhibits mTOR signaling pathway (important in cell growth/proliferation).
• Emerging second-line systemic treatment for recalcitrant life- or function-threatening IHs.
• Reports of successful use for large facial IHs failing β-blocker therapy.
• Adverse effects: mucositis, hyperlipidemia, headaches, hepatotoxicity, neutropenia.
• Laboratory monitoring necessary: CBC, serum creatinine, LFTs, lipid panels, sirolimus serum levels.
• Vincristine and recombinant interferon-α (2a and 2b): historical therapies for severe, recalcitrant IHs — no longer used due to complications (peripheral neuropathy and spastic diplegia, respectively).

Surgical Therapy

• Pulsed dye laser (PDL) — 585–600 nm wavelength, usually 0.45–1.5 ms pulse duration; effective for capillary malformations.
• May have some benefit for superficial IHs but risk of ulceration if used early in growth phase.
• Multiple sessions (usually every few weeks) required during proliferative phase.
• Given superior β-blocker efficacy, PDL currently NOT first-line for proliferating IHs.
• Often helpful for residual telangiectasias after propranolol therapy and/or involution.
• Adverse effects: pigmentary alteration, atrophic scarring, ulceration.
• Nd:YAG laser: also used, alone or with PDL; higher risk of scarring limits utility.
• Fractional CO2 laser: used to improve texture of residual atrophy/scarring after involution; multiple treatments typically required; may not be well tolerated without sedation.
• Surgical excision: for involuted/partially involuted lesions to remove fibrofatty tissue and redundant skin.
• Optimal timing depends on location, size, morphology (pedunculated vs sessile).
• Retrospective study of 112 IHs resected by a single surgeon: 87% located on head/neck; 38% of patients had received other treatments during proliferative phase; most excisions performed at 2–3 years of age.
• Excision during proliferative phase controversial, usually reserved for:

1. Function-threatening hemangioma (e.g. periocular lesion blocking visual axis, lip lesion interfering with feeding/speech) failing pharmacologic therapy.
2. Pharmacologic therapy believed to pose greater risk than surgical excision.

• Other appropriate early-surgery settings: pedunculated lesions where resection is inevitable; small, persistently ulcerated lesions failing conservative therapy.
• Goal: as normal an appearance as possible, weighing expected surgical scar against predicted involution course/outcome; management individualized.

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• Infants occasionally born with a fully developed hemangioma — congenital hemangiomas (CHs).
• Clinically, histologically, immunohistochemically, and genetically distinct from IHs.
• GLUT1-negative; different natural histories — most commonly RICH (rapidly involuting) or NICH (non-involuting) subtypes.
• Often have somatic gain-of-function mutations in GNAQ or GNA11 (encode G protein α-subunits) → increase signaling via the MAPK pathway.

Key Features of Infantile and Congenital Hemangiomas

• Infantile hemangioma: usually absent or precursor lesion at birth; rapid postnatal proliferation; slow spontaneous involution; more common in girls; lobular endothelial proliferation during proliferative phase, fibrous/fatty tissue during involution; positive GLUT1 and Lewis Y antigen.
• RICH: fully developed at birth; intrauterine proliferation; rapid involution during the first year* (*occasionally associated with thrombocytopenia during the neonatal period); equal prevalence in boys and girls; capillary lobules within fibrotic stroma containing thin-walled vessels, hemosiderin; negative GLUT1 and Lewis Y antigen.
• NICH: fully developed at birth; intrauterine proliferation then proportionate postnatal growth; do NOT involute spontaneously; tardive growth during childhood in ~10%; equal prevalence or slightly more common in girls; lobules of small, thin-walled vessels with a large central vessel, dilated dysplastic veins between lobules, "hobnailed" endothelial cells lining intralobular vessels; negative GLUT1 and Lewis Y antigen.
• Partially involuting congenital hemangiomas (PICHs): intermediate form undergoing incomplete involution.

RICH

• Intrauterine development with little/no postnatal growth; rapid involution within the first year.
• Equally common in boys and girls.
• Intrauterine growth noted by prenatal ultrasonography as early as 12 weeks' gestation; prenatal Doppler ultrasonography may show high vascularity/fast flow.
• Can appear at birth as: a raised violaceous mass with prominent radiating veins; a hemispheric nodule with coarse telangiectasias surrounded by a pale rim; or a firm, pink to violaceous plaque, often on the lower extremity.
• Small firm violaceous papules may be present on the surface; superimposed milia or hypertrichosis occasionally noted.
• Possible complications: necrosis, ulceration, transient thrombocytopenia, potentially life-threatening hemorrhage (may be heralded by focal crusting).

NICH

• Typically grows proportionately with the child; does NOT involute spontaneously.
• Slight female predominance; most often on trunk and extremities.
• Presents at birth as a well-circumscribed pink to blue–violet plaque or nodule with overlying coarse telangiectasias, surrounded by a pale or bluish rim, often with draining veins; "patch" subtype has a flat surface and minimal induration.
• Warm to palpation; may be painful.
• Diagnosis often established retrospectively when involution fails to occur.
• Up to 10% undergo tardive (delayed) growth, most often between 2 and 10 years of age; may develop red papules, overlying pyogenic granulomas, superficial bleeding.
• Some CHs that initially show regression soon after birth fail to fully involute — termed partially involuting congenital hemangioma (PICH).

Imaging and Pathology of CHs

• May be recognized by prenatal ultrasonography during the 2nd/3rd trimesters; misdiagnosis as other vascular anomalies (e.g. lymphatic or arteriovenous malformations) is common.
• Postnatal ultrasonography of RICH/NICH typically reveals dense vascularity with a fast-flow component.
• Compared to IH, CHs tend to have a more heterogeneous appearance with visible vessels and sometimes (especially in RICH) calcifications.
• MRI reveals features similar to IHs, though CHs may be less well-defined and occasionally show fat stranding.
• Histology/immunophenotype distinct from IHs: striking lobularity with densely fibrotic stroma, stromal hemosiderin deposits, focal thrombosis and sclerosis of capillary lobules, fewer mast cells, coexistence of proliferating vasculature with multiple thin-walled vessels.
• CHs lack immunoreactivity to GLUT1 and Lewis Y antigen; some tumors demonstrate zones of involution.

Treatment of CHs

• Most CHs do NOT require treatment.
• Medical therapies such as propranolol are generally NOT effective.
• Surgical excision may be an option for a well-defined NICH, although residual tumor and persistent pain are possible.

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Infantile Hemangioma

• Epidemiology: Most common benign tumor of infancy (affecting 4–5% of infants).
• Natural History: Absent or represented by a faint pale macule at birth → appears at 2–4 weeks → Rapid Proliferative Phase (growth up to 9–12 months) → Involution Phase (spontaneous regression: 50% involuted by 5 years, 90% by 9 years).
• PHACE Syndrome Association: Large segmental facial hemangiomas (segment 1):
• Posterior fossa brain malformations (Dandy-Walker)
• Hemangioma (segmental facial)
• Arterial cerebrovascular anomalies
• Cardiac defects / Coarctation of the aorta
• Eye anomalies
• Pharmacotherapy Guidelines:
• Oral Propranolol (2 to 3 mg/kg/day divided BID): First-line systemic treatment for complicated, life-threatening, or ulcerated hemangiomas (induces endothelial vasoconstriction, downregulates VEGF, and triggers apoptosis).
• Safety Monitoring: Monitor for hypoglycemia, bradycardia, and hypotension.

Pyogenic Granuloma (Lobular Capillary Hemangioma)

• Clinical: Rapidly growing, solitary, dome-shaped, friable red vascular papule/nodule that BLEEDS PROFUSELY WITH MINOR TRAUMA.
• Locations: Hands, fingers, lips, face, oral mucosa; common during pregnancy ("Granuloma Gravidarum").
• Treatment: Curettage of base followed by electrocautery of the feeding vessel.

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• Port-Wine Stain (Nevus Flammeus): Low-flow capillary malformation present at birth; pink-red flat patch that grows proportionally with the child, darkens to deep purple, and becomes cobblestoned/thickened in adulthood.
• Sturge-Weber Syndrome (Encephalotrigeminal Angiomatosis):
• Facial Port-Wine Stain involving the V1 (Ophthalmic) division of the Trigeminal Nerve.
• Associated with ipsilateral leptomeningeal angiomatosis, seizures, contralateral hemiparesis, intellectual disability, and glaucoma.
• Treatment: Early Pulsed Dye Laser (PDL 595 nm) therapy.

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